Atorvastatininteractions

See full prescribing information for details regarding concomitant use of LIPITOR with other drugs or grapefruit juice that increase the risk of myopathy and rhabdomyolysis.

Rifampin: May reduce atorvastatin plasma concentrations. Administer simultaneously with LIPITOR.

Oral Contraceptives: May increase plasma levels of norethindrone and ethinyl estradiol; consider this effect when selecting an oral contraceptive.

Digoxin: May increase digoxin plasma levels; monitor patients appropriately.

7.1 Drug Interactions that may

Increase the Risk of Myopathy and Rhabdomyolysis with LIPITOR LIPITOR is a substrate of CYP3A4 and transporters (e.g., OATP1B1/1B3, P-gp, or BCRP). LIPITOR plasma levels can be significantly increased with concomitant administration of inhibitors of CYP3A4 and transporters. Table 2 includes a list of drugs that may increase exposure to LIPITOR and may increase the risk of myopathy and rhabdomyolysis when used concomitantly and instructions for preventing or managing them. Table 2: Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with LIPITOR Cyclosporine or Gemfibrozil Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of LIPITOR and cyclosporine, an inhibitor of CYP3A4 and OATP1B1. Gemfibrozil may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine or gemfibrozil with LIPITOR. Intervention: Concomitant use of cyclosporine or gemfibrozil with LIPITOR is not recommended. Anti-Viral Medications Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of LIPITOR with many anti-viral medications, which are inhibitors of CYP3A4 and/or transporters (e.g., BCRP, OATP1B1/1B3, P-gp, MRP2, and/or OAT2). Cases of myopathy and rhabdomyolysis have been reported with concomitant use of ledipasvir plus sofosbuvir with LIPITOR. Intervention:

Concomitant use of tipranavir plus ritonavir or glecaprevir plus pibrentasvir with LIPITOR is not recommended.

In patients taking lopinavir plus ritonavir, or simeprevir, consider the risk/benefit of concomitant use with atorvastatin.

In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir, do not exceed LIPITOR 20 mg.

In patients taking nelfinavir, do not exceed LIPITOR 40 mg.

Consider the risk/benefit of concomitant use of ledipasvir plus sofosbuvir with LIPITOR.

Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Examples: Tipranavir plus ritonavir, glecaprevir plus pibrentasvir, lopinavir plus ritonavir, simeprevir, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir, letermovir, nelfinavir, and ledipasvir plus sofosbuvir. Select Azole Antifungals or Macrolide Antibiotics Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of LIPITOR with select azole antifungals or macrolide antibiotics, due to inhibition of CYP3A4 and/or transporters. Intervention: In patients taking clarithromycin or itraconazole, do not exceed LIPITOR 20 mg. Consider the risk/benefit of concomitant use of other azole antifungals or macrolide antibiotics with LIPITOR. Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Examples: Erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole. Niacin Clinical Impact: Cases of myopathy and rhabdomyolysis have been observed with concomitant use of lipid modifying dosages of niacin (≥1 gram/day niacin) with LIPITOR. Intervention: Consider if the benefit of using lipid modifying dosages of niacin concomitantly with LIPITOR outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Fibrates (other than Gemfibrozil) Clinical Impact: Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with LIPITOR. Intervention: Consider if the benefit of using fibrates concomitantly with LIPITOR outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Colchicine Clinical Impact: Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with LIPITOR. Intervention: Consider the risk/benefit of concomitant use of colchicine with LIPITOR. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Grapefruit Juice Clinical Impact: Grapefruit juice consumption, especially excessive consumption, more than 1.2 liters/daily, can raise the plasma levels of atorvastatin and may increase the risk of myopathy and rhabdomyolysis. Intervention: Avoid intake of large quantities of grapefruit juice, more than 1.2 liters daily, when taking LIPITOR.

7.2 Drug Interactions that may

Decrease Exposure to LIPITOR Table 3 presents drug interactions that may decrease exposure to LIPITOR and instructions for preventing or managing them.

Table 3: Drug Interactions that may Decrease Exposure to LIPITOR Rifampin Clinical Impact: Concomitant administration of LIPITOR with rifampin, an inducer of cytochrome P450 3A4 and inhibitor of OATP1B1, can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, delayed administration of LIPITOR after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.

Intervention: Administer LIPITOR and rifampin simultaneously.

7.3 LIPITOR

Effects on Other Drugs Table 4 presents LIPITOR’s effect on other drugs and instructions for preventing or managing them.

Table 4: LIPITOR Effects on Other Drugs Oral Contraceptives Clinical Impact: Co-administration of LIPITOR and an oral contraceptive increased plasma concentrations of norethindrone and ethinyl estradiol.

Intervention: Consider this when selecting an oral contraceptive for patients taking LIPITOR.

Digoxin Clinical Impact: When multiple doses of LIPITOR and digoxin were co-administered, steady state plasma digoxin concentrations increased.

Intervention: Monitor patients taking digoxin appropriately.

Drug Interactions Atorvastatin is a substrate of the hepatic transporters, OATP1B1 and OATP1B3 transporter. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the efflux transporter BCRP, which may limit the intestinal absorption and biliary clearance of atorvastatin.

Table 5: Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin Co-administered drug and dosage regimen Atorvastatin Dosage (mg) Ratio of AUC Represents ratio of treatments (co-administered drug plus atorvastatin vs. atorvastatin alone). Ratio of Cmax See Sections 5.1 and 7 for clinical significance. Cyclosporine 5.2 mg/kg/day, stable dose 10 mg QD Once daily for 28 days 8.69

10.66 Tipranavir 500 mg BID

Twice daily /ritonavir 200 mg BID, 7 days 10 mg SD Single dosage 9.36 8.58 Glecaprevir 400 mg QD /pibrentasvir 120 mg QD, 7 days 10 mg QD for 7 days 8.28

22.00 Telaprevir 750 mg q8h

Every 8 hours, 10 days 20 mg SD 7.88 10.60, The dose of saquinavir plus ritonavir in this study is not the clinically used dose. The increase in atorvastatin exposure when used clinically is likely to be higher than what was observed in this study. Therefore, caution should be applied and the lowest dose necessary should be used. Saquinavir 400 mg BID /ritonavir 400 mg BID, 15 days 40 mg QD for 4 days 3.93 4.31 Elbasvir 50 mg QD /grazoprevir 200 mg QD, 13 days 10 mg SD 1.94 4.34 Simeprevir 150 mg QD, 10 days 40 mg SD 2.12 1.70 Clarithromycin 500 mg BID, 9 days 80 mg QD for 8 days 4.54 5.38 Darunavir 300 mg BID /ritonavir 100 mg BID, 9 days 10 mg QD for 4 days 3.45 2.25 Itraconazole 200 mg QD, 4 days 40 mg SD 3.32 1.20 Letermovir 480 mg QD, 10 days 20 mg SD 3.29 2.17 Fosamprenavir 700 mg BID /ritonavir 100 mg BID, 14 days 10 mg QD for 4 days 2.53 2.84 Fosamprenavir 1400 mg BID, 14 days 10 mg QD for 4 days 2.30 4.04 Nelfinavir 1250 mg BID, 14 days 10 mg QD for 28 days 1.74

2.22 Grapefruit

Juice, 240 mL QD, Greater increases in AUC (ratio of AUC up to 2.5) and/or Cmax (ratio of Cmax up to 1.71) have been reported with excessive grapefruit consumption (≥ 750 mL-1.2 liters per day). 40 mg SD 1.37 1.16 Diltiazem 240 mg QD, 28 days 40 mg SD 1.51

1.00 Erythromycin 500 mg QID

Four times daily, 7 days 10 mg SD 1.33 1.38 Amlodipine 10 mg, single dose 80 mg SD 1.18 0.91 Cimetidine 300 mg QID, 2 weeks 10 mg QD for 2 weeks 1.00 0.89 Colestipol 10 g BID, 24 weeks 40 mg QD for 8 weeks NA 0.74 Ratio based on a single sample taken 8-16 h post dose. Maalox TC ® 30 mL QID, 17 days 10 mg QD for 15 days 0.66 0.67 Efavirenz 600 mg QD, 14 days 10 mg for 3 days 0.59

1.01 Rifampin 600 mg QD, 7 days (co‑administered)

Due to the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. 40 mg SD 1.12 2.90 Rifampin 600 mg QD, 5 days (doses separated) 40 mg SD 0.20 0.60 Gemfibrozil 600 mg BID, 7 days 40 mg SD 1.35 1.00 Fenofibrate 160 mg QD, 7 days 40 mg SD 1.03

1.02 Boceprevir 800 mg TID

Three times daily, 7 days 40 mg SD 2.32

2.66 Table 6:

Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs Atorvastatin Co-administered drug and dosage regimen Drug/Dosage (mg) Ratio of AUC Ratio of Cmax 80 mg QD Once daily for 15 days Antipyrine, 600 mg SD Single dosage 1.03 0.89 80 mg QD for 10 days See Section 7 for clinical significance. Digoxin 0.25 mg QD, 20 days 1.15 1.20 40 mg QD for 22 days Oral contraceptive QD, 2 months - norethindrone 1 mg - ethinyl estradiol 35 µg 1.28 1.19 1.23 1.30 10 mg SD Tipranavir 500 mg BID Twice daily /ritonavir 200 mg BID, 7 days 1.08 0.96 10 mg QD for 4 days Fosamprenavir 1400 mg BID, 14 days 0.73 0.82 10 mg QD for 4 days Fosamprenavir 700 mg BID /ritonavir 100 mg BID, 14 days 0.99 0.94 LIPITOR had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.